7rco
Crystal structure of human TGF-beta-2 bound to 4A11.V2 Fab
Structural highlights
DiseaseTGFB2_HUMAN Note=A chromosomal aberration involving TGFB2 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with HDAC9. Defects in TGFB2 are the cause of Loeys-Dietz syndrome 4 (LDS4) [MIM:614816. An aortic aneurysm syndrome with widespread systemic involvement. LDS4 is characterized by arterial tortuosity, aortic dissection, intracranial aneurysm and subarachnoid hemorrhage, hypertelorism, bifid uvula, pectus deformity, bicuspid aortic valve, arachnodactyly, scoliosis, foot deformities, dural ectasia, joint hyperflexibility, and thin skin with easy bruising and striae.[1] FunctionTGFB2_HUMAN TGF-beta 2 has suppressive effects on interleukin-2 dependent T-cell growth. Publication Abstract from PubMedAntibody function is typically entirely dictated by the Complementarity Determining Regions (CDRs) that directly bind to the antigen, while the framework region acts as a scaffold for the CDRs and maintains overall structure of the variable domain. We recently reported that the rabbit monoclonal antibody 4A11 (rbt4A11) disrupts signaling through both TGFbeta2 and TGFbeta3 (Sun et al. in Sci Transl Med, 2021. https://doi.org/10.1126/scitranslmed.abe0407 ). Here, we report a dramatic, unexpected discovery during the humanization of rbt4A11 where, two variants of humanized 4A11 (h4A11), v2 and v7 had identical CDRs, maintained high affinity binding to TGFbeta2/3, yet exhibited distinct differences in activity. While h4A11.v7 completely inhibited TGFbeta2/3 signaling like rbt4A11, h4A11.v2 did not. We solved crystal structures of TGFbeta2 complexed with Fab fragments of h4A11.v2 or h4A11.v7 and identified a novel interaction between the two heavy chain molecules in the 2:2 TGFb2:h4A11.v2-Fab complex. Further characterization revealed that framework residue variations at either position 19, 79 or 81 (Kabat numbering) of the heavy chain strikingly converts h4A11.v2 into an inhibitory antibody. Our work suggests that in addition to CDRs, framework residues and interactions between Fabs in an antibody could be engineered to further modulate activity of antibodies. Dramatic activation of an antibody by a single amino acid change in framework.,Liang WC, Yin J, Lupardus P, Zhang J, Loyet KM, Sudhamsu J, Wu Y Sci Rep. 2021 Nov 16;11(1):22365. doi: 10.1038/s41598-021-01530-w. PMID:34785671[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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